Postpartum depression is a serious condition that, if not recognized and treated timely, not only has deleterious effects on the mother but also poses a serious risk for the mother-infant relationship and ultimately infant developmental outcome. Recent evidence shows that the clinical features of postpartum depression differ from depression that occurs outside the postpartum period, with the former being characterized primarily by cognitive and motivational disturbances, including impairments in attention and cognitive flexibility, as well as reduced behavioral activation and effort-related functions. Although the clinical literature consistently relates postpartum depression to compromised parenting, to date, no studies have examined the neurobiological mechanisms by which parenting is disrupted in postpartum depression. A substantial body of work implicates a role for altered mesocorticolimbic dopamine (DA) neurotransmission in the pathophysiology of cognitive and motivational symptoms of depression. The studies in the present proposal will examine whether alterations in mesocorticolimbic DA function underlie the cognitive and motivational impairments in postpartum depression that lead to deficits in parenting. These studies will use the Wistar-Kyoto (WKY) genetic rat model of depression. Preliminary data demonstrate that the WKY strain recapitulates, with considerable face validity, the major clinical features of depression in new mothers, including the cognitive, motivational and parenting disturbances. The first group of experiments will use maternal behavior analysis with simultaneous microdialysis sampling to examine whether alterations in DA release in discrete cortical and striatal structures critically involved in cognitive and motivational processes, are related to the deficient maternal response of WKY females. The second group of experiments will use a symptom-based approach to dissect the specific contribution of cognitive and motivational dysfunctions to parenting disturbances. These studies will use site- specific DA receptor blockade within cortical and striatal structures in control strains and behavioral tasks that specifically assess cognitive and effort-related symptom domains, in combination with detailed analysis of maternal behavior. The third group of experiments will evaluate the therapeutic efficacy of adenosine A2A receptor antagonism as a novel treatment strategy for postpartum depression. Emerging evidence indicates that the neuromodulator adenosine, particularly through actions on adenosine A2A receptors, modulates behavioral functions associated with the mesocorticolimbic DA system, including cognitive and motivational processes. My published work supports the potential of the A2A receptor as a novel therapeutic target by demonstrating that adenosine A2A receptor antagonism reversed the disruptive effects of DA receptor blockade on the effort-related instrumental output of male rats and on the maternal behavior of postpartum rats. PUBLIC HEALTH RELEVANCE: Postpartum depression is one of the most prevalent and severe mental illnesses affecting women, and is of serious public health concern because of its demonstrated adverse impact on the mother's health and parenting capacities, with effects on the infant's socio-emotional and cognitive developmental outcome. The potential impacts of postpartum depression affect not only the well-being of the mother, her infant, and her family, but also have consequences for social productivity and health care costs. The proposed studies represent the first preclinical attempt to examine the neurobiological underpinnings of the cognitive and motivational symptom dimensions that are central to postpartum depression and likely lead to deficits in parenting, as well as to test a novel treatment that is specifically tareted toward ameliorating them.